The boron difluoride chelate of quinolone-3-carboxylic acid is an important intermediate for the preparation of quinolone antibacterial agents such as Norfloxacin, Ciprofloxacin, Ofloxacin, Levefloxacin, Gatifloxacin, Difloxacin, Perfloxacin and Enrofloxacin. The chelate I is usually prepared by the reaction of quinolone-3-carboxylic acid derivative II and fluoroboric acid (HBF4) or trifluoroborane (BF3):

A byproduct of the reaction is hydrogen fluoride, a highly corrosive acid which can cause extremely painful and slow-healing burns and ulcers in humans. It etches glass and corrodes most substances except lead, polyethylene wax, and platinum (Encyclopedia of Reagents for Organic Synthesis, vol. 4, p. 2699, hereby incorporated as reference). These deficiencies dramatically limit the application of this reaction, especially for commercial scale production.
It was reported in the prior art that quinolone-3-carboxylic acid or its esters react with aqueous fluoroboric acid solution to form the chelate, for instance, those reported in WO 2004/101527 and U.S. Pat. No. 4,980,470. However, when these reactions are performed in glass-flasks or glass-lined reactors, the hydrogen fluoride formed reacts with the glass, generating insoluble inorganic fluoro-silicon compounds which are very difficult to remove from the product. The hydrogen fluoride byproduct also severely damages flasks or reactors and poses serious safety and operational problems. When these reactions are performed in non-glass equipment, such as stainless steel or Hastelloy® reactors, the reactions only produce quinolone-3-carboxylic acid (via ester hydrolysis or recovered starting material), and chelate formation is not observed.
It was also reported in WO 2005/047260 that the boron difluoride chelate of quinolone-3-carboxylic acid was formed from a quinolone-3-carboxylic acid silyl ester. However, in this process, quinolone-3-carboxylic acid has to be pre-converted into its silyl ester with a silylating agent such as hexamethyidisilazane or chlorotrimethylsilane.
It is therefore an object of this invention to provide a more industrially applicable process for the preparation of the boron difluoride chelate of quinolone-3-carboxylic acid which overcomes the deficiencies of the prior art processes.
It is a further object of the invention to provide silicon-containing compounds containing at least one silicon-oxygen bond which are useful in the formation of the boron difluoride chelate of quinolone-3-carboxylic acid.
It is a further object of the invention to provide a process for converting the boron difluoride chelate of quinolone-3-carboxylic acid into quinolone antibacterial agents.
Further and other objects of the invention will become apparent to those skilled in the art when considering the following summary of the invention and the more detailed description of the embodiments of the invention described herein.